The present invention relates to agents and methods for blocking deleterious T cell mediated immune reactions. Such reactions occur in autoimmune diseases, such as for example, multiple sclerosis (MS), rheumatoid arthritis, systemic lupus erythematosis, psoriasis, diabetes, and allergies. Such reactions also occur during rejection of transplants.
Two types of signals are required for T cell activation and proliferation. The first, which gives specificity to the immune response, involves an interaction between the T-cell receptor/CD3 complex and an antigenic peptide presented by major histocompatibility complex (MHC) class I or class II proteins on the surface of an antigen-presenting cell (APC). The second type of signal, called a costimulatory signal, involves interaction between receptor-ligand pairs expressed on the surface of APCs and T cells. Antigenic stimulation in the absence of costimulation mechanisms induces a state of unresponsiveness or anergy and eventual cell death by apoptosis in the responding T cells. Thus, antigenic stimulation in the presence of costimulation prevents anergy and cell death, thereby promoting cell survival.
CD 28 is one of the principal T cell costimulatory receptors. CD28 binds APC costimulatory ligands B7.1(CD80) and B7.2(CD86). CD28 is a transmembrane homodimer that is constitutively expressed on 90% of mammalian CD4+ T cells. Upon binding to the B7 family of molecules, CD28 delivers a powerful costimulatory signal for T cell activation and clonal expansion. Engagement of CD28 by its ligands B7-1 or B7-2 on the surface of APCs initiates a signaling cascade culminating in cytokine production and expansion of specific T-cells.
T cells also express cytotoxic-T-lymphocyte antigen 4, CTLA-4 (CD152), a close relative of CD28. In contrast to CD28, CTLA-4 is not expressed by naive T cells but is rapidly induced after T cell activation. Analogous to CD28, CTLA-4 also binds the B-7 family of molecules, albeit with higher avidity than CD28. Engagement of CTL4 with the B7 ligands transmits a negative signal to the T cells, thus terminating the immune response.
The critical role played by the B7/CD28:CTLA-4 costimulatory interaction in determining the fate of immune responses (activation vs anergy/apoptosis) makes it an attractive target for therapeutic immunomodulation in a wide range of autoimmune diseases. Recently, it has been shown that administration of monoclonal antibodies to B7 molecules and CTLA-4 Ig fusion protein ameliorate autoimmune diseases in various animal models, including (EAE) an animal model for MS, diabetes and systemic lupus erythematosis. However, these results depend upon the timing of antibody administration. For example, CTLA-4 Ig was not effective in blocking already established EAE, and anti B7-2 mAB and anti CTLA-4 mAB exacerbate the disease. Moreover, the value of such antibodies as effective therapeutic agents is limited by virtue of their inherent immunogenicity and poor penetration across tissue barriers.
Accordingly, it is desirable to have additional methods and agents which can be used to block deleterious T-cell mediated immune reaction and to ameliorate the symptoms of diseases and disorders associated with such reactions.